This invention is concerned with antibacterial and intermediate substances which are derived by selective chemical transformation of partially hydrolyzed tylosin and related macrolide derivatives in which only the mycaminose sugar remains attached to the macrocyclic lactone ring. Compounds having particular utility as antibacterial agents have C-6 side chain aldehyde converted to a hydrazone, C-3 ring hydroxy group acylated, and/or C-14 hydroxymethyl group converted to a sulfonate or carboxylate ester, or to a halomethyl, aminomethyl, sulfonamidomethyl or carboxamidomethyl group. Compounds whose prime utility is as intermediates have side chain aldehyde group protected as an acetal, mycaminose sugar hydroxyls protected as a carboxylate ester and/or C-14 hydroxymethyl converted to a formyl or azidomethyl group.
A large number of macrolide antibiotics and derivatives are known to the medicinal sciences, some such as CP-56,063 and CP-56,064 below, only recently discovered.
One of the starting materials for the present invention is tylosin stripped of two of its sugars, so-called desmycarosyl desmycinosyl tylosin, desmycinosyl tylonide or mycaminosyl tylonolide. More systematically, this compound is named 5-(3,6-dideoxy-3-dimethylamino-beta-D-glucopyrnosyloxy)-6-formylmethyl-3-h ydroxy-14-hydroxymethyl-4,8,12-trimethyl-9-oxo-10,12-heptadecadien-15-olide . This tylosin degradation product is of the formula (I) below, but has A=OH, Y=oxygen and R.sup.1 =H. It is reported to be a biosynthetic precursor of tylosin, Omura et al., J. Antibiot. 31, pp. 254-256, 1978. Although originally and vaguely reported as "antibacterial", the prior art has been long silent concerning the specific activity of this compound. Only now has the actual utility and value of this compound as an antibacterial agent been recognized.
Other starting materials, useful in the present invention are derived from CP-56,063 and CP-56,064 via chemical processes and intermediates described below. Similar chemical processes have been previously reported for the selective cleavage of the mycinose sugar from tylosin, Nagel and Vincent, J. Org. Chem. 44, pp. 2050-2052, 1979. The preparation by fermentation and isolation of CP-56,063 and CP-56,064 are also fully disclosed herein.
Umezawa et al., U.S. Pat. Nos. 4,196,280 and 4,255,564 have generally described macrolide derivatives converted to cyclic acetals, then hydrolyzed stepwise, first removing all but mycaminose and finally the mycaminose to yield the acetal of the aglycone. Among the infinity of compounds claimed in U.S. Pat. No. 4,255,564 are compounds of the formula (III) and (IV), but wherein B=R.sup.6 =H, A.sup.1 =OH, R.sup.1 =H or "an acyl group" and HC(OR.sup.7).sub.2 is "an aldehyde group protected by a cyclic acetal". Although claimed, there is no teaching in that patent which would permit preparation of the present compounds of the formula (III) and (IV), wherein B is H, A.sup.1 is OH, R.sup.1 an acyl group and HC(OR.sup.7) represents an acetal, since the appropriate precursor fermentation macrolides having R.sup.1 as acyl required by Umezawa et al. are not known in the present series.
The Umezawa et al. compounds are indicated to be useful for "introducing new sugar moieties or substituents". However the only species disclosed and claimed by Umezawa et al. which is closely related to compounds of the present invention is the compound having the formula (III), but with B=R.sup.1 =R.sup.6 =H, A.sup.1 =OH and both R.sup.7 together=--(CH.sub.2).sub.2 --. This compound, which appears to be twice claimed (claims 11 and 14 of U.S. Pat. No. 4,255,564) is no more than further degraded by removal of the mycaminose sugar. No method is taught for reintroduction of a sugar or any other group, selectively or otherwise, into either one of these polyhydroxy compounds (mycaminosyl tylonolide acetal and tylonolide acetal).
The corresponding dimethylacetal, of the formula (III) below, but having B=R.sup.1 =R.sup.6 =H, A.sup.1 =OH and R.sup.7 =CH.sub.3 has also been previously reported as an uncharacterized intermediate in the preparation of the corresponding tetrahydro derivative by Omura et al., Tetrahedron Letters No. 12, pp. 1045-1048, 1977. No utility was reported for either this dimethyl acetal or its tetrahydro derivative.
Without a stated utility, Umezawa et al. also appear to claim the aldehydic compound of the formula (I) but wherein A=OH, Y=oxygen and R.sup.1 =H (claim 13 of U.S. Pat. No. 4,255,564), one of the starting materials employed in the present invention. This product, discussed above and commonly referred to in the literature as mycaminosyl tylonolide, was first reported by Morin and Gorman, Tetrahedron Letters No. 34, pp. 2339-2345 (1964), even before the structure of tylosin was fully established.
Recently Ganguly et al. have reported certain antibacterial hydrazone derivatives of rosaramicin, a macrolide antibiotic having a structure substantially different from the present tylosin/CP-56,063 derivatives.